The control of peripheral T cell survival is critical to the maintenance of an effective peripheral immune repertoire. Some aspects of T cell survival appear to be linked to the state of T cell activation. T cell activation is initiated by the engagement of the T cell receptor/CD3 complex (TCR/CD3) by a peptide-antigen bound to a major histocompatibility complex (MHC) molecule on the surface of an antigen-presenting cell (APC) (Schwartz, R. H. (1990) Science 248, 1349). While this is the primary signal in T cell activation, other receptor-ligand interactions between APCs and T cells are required for complete activation. For example, TCR stimulation in the absence of other molecular interactions can induce a state of anergy, such that these cells can not respond to full activation signals upon restimulation (Schwartz, R. H. (1990) Science 248, 1349; Harding, F. A., McArthur J. G., Gross, J. A., Raulet, D. H., and Allison, J. P. (1992). Nature 356, 607.). Alternatively, T cells have been shown to die by programmed cell death (PCD) when activated by TCR engagement alone (Webb, S., Morris, C., and Sprent, J. (1990) Cell 63, 1249; Kawabe, Y., and Ochi, A. (1991) Nature 349, 245; Kabelitz, D., and Wesselborg, S. (1992) Int. Immunol 4, 1381; Groux, H., Monte, D., Plouvier, B., Capron, A., and Ameisen, J-C (1993). Eur. J. Immunol. 23, 1623).
There are multiple receptor-ligand interactions which take place between the T cell and the APC. Many interactions are adhesive in nature and reinforce the contact between the two cells (Springer, T. A., Dustin, M. L., Kishimoto, T. K., and Marlin, S. D. (1987) Annul. Rev. Immunol. 5, 223), while other interactions transduce additional activation signals to the T cell (Bierer, B. E., and Burakoff, S. J. (1991) Adv. Cancer Res. 56, 49). CD28, a surface glycoprotein present on 80% of peripheral T cells in humans, has been shown to be an important costimulatory receptor (June, C. H., Bluestone, J. A., Nadler, L. M. and Thompson, C. B. (1994) Immunol. Today 15, 321; Linsley, P. S. Ledbetter, J. A. (1993) Annu. Rev. Immunol. 11, 191). A costimulatory signal is transduced through CD28 when T cells encounter an antigen-presenting cell expressing either of the CD28 ligands B7-1 or B7-2.
Costimulation of T cells has been shown to affect multiple aspects of T cell activation (June, C. H., Bluestone, J. A., Nadler, L. M. and Thompson, C. B. (1994) Immunol. Today 15, 321). Costimulation will lower the concentration of anti-CD3 required to induce a proliferative response in culture (Gimmi, C. D, Freeman, G. J., Gribben, J. G., Sugita, K., Freedman, A. S., Morimoto, C., and Nadler, L. M. (1991). Proc. Natl. Acad. Sci. USA 88, 6575). CD28 costimulation also markedly enhances the production of lymphokines by helper T cells through transcriptional and post-transcriptional regulation of gene expression Lindsten, T., June, C. H., Ledbetter, J. A., Stella, G., and Thompson, C. B. (1989) Science 244, 339; Fraser, J. D., Irving, B. A., Crabtree, G. R., and Weiss, A. (1991) Science 251, 313), and can activate the cytolytic potential of cytotoxic T cells. Inhibition of CD28 costimulation in vivo can block xenograft rejection and allograft rejection is significantly delayed (Lenschow, D. J., Zeng, Y., Thistlethwaite, J. R., Montag, A., Brady, W., Gibson, M. G., Linsley, P. S., and Bluestone, J. A. (1992) Science 257, 789; Turka, L. A., Linsley, P. S., Lin, H., Brady, W., Leiden, J. M., Wei, R-Q., Gibson, M. L., Zheng, X-G., Mydral, S., Gordon, D., Bailey, T., Bolling, S. F., and Thompson, C. B. (1992) Proc. Natl. Acad. Sci. USA 89, 11102). In addition, transfection of B7 into a tumor cell line facilitates recognition and prevention of tumor growth (Chen, L., Ashe, S., Brady, W. A., Hellstrom, I., Hellstrom, K. E., Ledbetter, J. A., McGowan, P., and Linsley P. S. (1992) Cell 71, 1093; Townsend, S. E., and Allison, J. P. (1993) Science 259, 368).
Until recently, relatively little has been known about how peripheral T cell survival is controlled. Studies suggest that mitogen-activation of T cells enhances their resistance to programmed cell death (PCD) initiated by treatment with such agents as radiation (Schrek, R., and Stefani, S. (1964) J. Nat. Cancer Inst. 32, 507; Lowenthal, J. W. and Harris, A. W. (1985) J. Immunol. 135, 1119; Stewart, C. C., Stevenson, A. P., and Habbersett, R. C. (1988) J. Radiat. Biol. 53, 77). In contrast, T cell activation through the TCR alone has been reported to increase the susceptibility of T cells to undergo PCD (Kabelitz, D., and Wesselborg, S. (1992) Int. Immunol 4, 1381; Groux, H., Monte, D., Plouvier, B., Capron, A., and Ameisen, J-C (1993). Eur. J. Immunol. 23, 1623).
Recently, several genes have been identified that appear to play roles in regulating T cell survival. The survival of quiescent lymphocytes in the mouse is dependent on the expression of the bcl-2 gene (Nakayama, K-I., Nakayama, K., Negishi, I., Kuida, K., Shinkai, Y., Louie, M. C. Fields, L. E., Lucas, P. J. Stewart, V., Alt, F. W., and Loh, D. Y. (1993) Science 261, 1584). Animals deficient in the bcl-2 gene have T cells with an increased susceptibility to undergo PCD when placed in culture. Bcl-2-deficient animals become profoundly lymphopenic within the first few weeks of life (Veis, D. J., Sorenson, C. M., Shutter, J. R., and Korsmeyer, S. J. (1993a) Cell 75, 229). In contrast, animals with mutations in the Fas cell surface receptor fail to clear the excess immune cells generated in the course of an immune response (Watanabe-Fukunaga, R., Brannan, C. I., Copeland, N. G., Jenkins, N. A., and Nagata, S. (1992) Nature 356, 314). Fas-deficient animals ultimately develop profound autoimmune disease. These data suggest that T cell survival may be as tightly regulated as T cell proliferation.
Inappropriate regulation of T cell death may result in immune system disorders (e.g., immunodeficiencies or autoimmunity). Moreover, infection of T cells with certain infectious microorganisms results in killing of the T cells. In particular, infection of T cells with human immunodeficiency virus (HIV) results in cell death induced by programmed cell death (Gougon, M.-L. and Montagnier, L. (1993) Science 260, 1269). Thus, methods for controlling T cell death and in particular inhibiting such death, are needed.